The liver is located at the apex of the portal circulation and is the first recipient of a large nunber of hormones secreted by the gut and pancreas. However, there has been little assessment of the effects of these gastrointestinal hormones on hepatic function. Specific aims of this proposal are to determine the influence of gastrointestinal hormones on regulation of hepatic drug metabolism and hepatic bile formation. After 96 hours of systemic or portal vein infusions of insulin, somatostatin, glucagon, gastrin, or CCK, clearance of 14C-pentobarbital will be measured and microsomal levels of cytochrome P-450 and metabolism of meperidine, pentobarbital and benzpyrene will be determined. Isolated hepatocytes will be cultured for up to 5 days in the presence of study hormones to determine if cytochrome P-450 levels and mixed function oxidase activity are influenced by gastrointestinal hormones in vitro. Culture studies are less physiological, but circumvent indirect effects produced by many GI hormones in vivo. Glucose concentration in culture medium will be varied to determine if variation of this parameter affects hepatic drug metabolism. Preliminary data from this laboratory suggest that bolus injections of various GI hormones produce significant changes in bile flow and hepatic bile acid transport. In proposed experiments, vasoactive intestinal peptide (VIP), bombesin, thyrotropin-releasing hormone (TRH) and somatostatin will be infused into the portal vein catheter of isolated perfused rat liver preparations; bile flow, 14C-erythritol clearance and bile acid output will be monitored during control and infusion periods. Effects of varied concentrations of VIP, bombesin, TRH, somatostatin, CCK and secretin on bile acid uptake will be determined in freshly isolated hepatocytes and in liver cells cultured for 48 hours in the presence of study hormones. Basic research into effects of GI hormones on hepatic regeneration has led to encouraging preliminary studies employing insulin and glucagon infusions to treat severe alcoholic hepatitis. Altered hepatic exposure to gastrointestinal hormones may contribute to liver enzyme abnormalities and the increased frequency of gallstones seen in patients receiving parenteral hyperalimentation, diabetics and obese subjects. Further understanding of the interrelationships between hepatic function and GI hormones may suggest future methods of treatment of these common clinical problems.